Differential effects of cyclooxygenase inhibitors on intracerebroventricular colchicine-induced dysfunction and oxidative stress in rats

Alzheimer's disease is a progressive neurological and psychiatric disorder. Oxidative stress and neuroinflammation have been implicated in pathophysiology of Alzheimer's disease. Inflammatory cells, such as astrocytes and microglia, are activated in areas of the brain affected by amyloid plaques and inflammatory mediators including cytokines, chemokines, prostaglandins, oxygen free radicals and reactive nitrogen species may have a crucial role in Alzheimer's disease pathogenesis. Central administration of colchicine, a microtubule-disrupting agent, causes loss of cholinergic neurons and cognitive dysfunction that is associated with excessive free radical generation. The present study was aimed to evaluate the effects of cyclooxygenase inhibitors against colchicine-induced cognitive dysfunction and oxidative stress in rats. Following intracerebroventricular (i.c.v.) administration of colchicine (15 microg/5 microl), rats exhibited poor retention of memory in Morris water maze and elevated plus maze task paradigms and oxidative stress in rats. Chronic treatment with naproxen (per se; 20 and 40 mg/kg, p.o.) or valdecoxib (per se; 5 and 10 mg/kg, p.o.) daily respectively for a period of 25 days beginning 4 days prior to colchicine injection significantly improved colchicine-induced cognitive impairment. Intracerebroventricular colchicine injection resulted in free radical generation characterized by alterations in oxidative stress markers with a significant increase in malondialdehyde and nitrite levels and depletion of reduced glutathione levels in the brains of rats. It also caused a decrease in acetylcholinesterase activity. Besides, improving cognitive dysfunction, chronic administration of cyclooxygenase inhibitors (naproxen and valdecoxib) significantly reduced elevated malondialdehyde, nitrite levels and restored reduced glutathione levels and acetylcholinesterase activity. The results of the present study indicated that naproxen (per se; 20 and 40 mg/kg, p.o.) or valdecoxib (per se; 5 and 10 mg/kg, p.o.) treatment has a neuroprotective role against colchicine-induced cognitive impairment and associated oxidative stress. The present findings further support the potential use of cyclooxygenase inhibitors in treatment of neurodegenerative diseases such as Alzheimer's disease.     

Effect of hyperosmotic xylitol on gastric secretion in the rat: lack of influence of cyclooxygenase inhibitors

The effects of hyperosmotic solutions of xylitol were tested on acid and bicarbonate outputs from the rat stomach as well as on acid back-diffusion. Hyperosmotic solutions were instilled into anesthetized rats by an esophageal cannula and drained through a duodenal catheter. Spontaneously secreting and histamine-stimulated rats were used in different experiments. Hyperosmotic xylitol solutions at concentrations of 18.4% or higher produced graded inhibitions of the histamine-induced acid secretion. A 34.5% xylitol solution also inhibited spontaneous acid secretion. The same solution also caused a certain degree of acid back-diffusion and increased output of bicarbonate. Neither the inhibition acid secretion nor stimulation of bicarbonate output were affected by cyclooxygenase inhibitors indomethacin or flufenamic acid. It is concluded that hyperosmotic xylitol reduces gastric acidity by three mechanisms namely inhibition of acid secretion, increased bicarbonate output and increased back-diffusion of acid. None of these mechanisms seem to depend on prostaglandin biosynthesis.     

Anti-inflammatory and side effects of cyclooxygenase inhibitors

Nonsteroidal anti-inflammatory drugs (NSAIDs) are the most commonly used drugs in inflammatory diseases, since they are effective in management of pain, fever, redness, edema arising as a consequence of inflammatory mediator release. Studies have shown that both therapeutic and side effects of NSAIDs are dependent on cyclooxygenase (COX) inhibition. COX isoforms have been named constitutive (COX-1) and inducible (COX-2). COX-1 catalyzes formation of cytoprotective prostaglandins in thrombocytes, vascular endothelium, stomach mucosa, kidneys, pancreas, Langerhans islets, seminal vesicles, and brain. Induction of COX-2 by various growth factors, proinflammatory agents, endotoxins, mitogens, and tumor agents indicates that this isoform may have a role in induction of pathological processes, such as inflammation. It is well known that therapy with COX inhibitors is associated with a number of side effects including gastrointestinal erosions, and renal and hepatic insufficiency. Such critical adverse reactions are mostly dependent on COX-1 inhibition. As a result of research focused on reduction of the adverse effects of NSAIDs, selective COX-2 inhibitors, such as celecoxib and rofecoxib have been developed. However, many data demonstrate that mechanisms of action of these drugs are multidirectional and complex. These drugs or their derivatives, which belong to the same group, have distinct pharmacological effects, side effects and potencies which implies that there may be more than two, five or even tens of COX isoforms.     

Renal effects of cyclooxygenase inhibitors in volume-depleted dogs

Objective: The objective of this study was to investigate the renal effects of celecoxib, a cyclooxygenase-2 (COX-2) specific nonsteroidal anti-inflammatory drug (NSAID). Subjects and treatment: Six volume-depleted, conscious, chronically instrumented dogs received four treatments using a cross-over design, with at least 13 days between treatments. An i.v. bolus dose (3, 10, and 30 mol/kg) of vehicle, indomethacin, celecoxib, or 6-MNA, the active metabolite of nabumetone, were administered with an hour between doses. Methods: Renal function was assessed at baseline and 30 min after each dose. Results: Treatment with indomethacin or celecoxib resulted in a dose-dependent reduction in renal plasma flow (RPF), glomerular filtration rate (GFR), urine flow, sodium excretion, and fractional sodium excretion. GFR was reduced by 27% with 30 mol/kg indomethacin (p < 0.05) and by 58% with 30 mol/kg celecoxib (p < 0.5). Similarly, RPF was significantly (p < 0.05) reduced by 33% and 65% with 30 mol/kg indomethacin and celecoxib, respectively. Reductions in renal function with celecoxib occurred at a therapeutic index (determined by comparison anti-edemic activities of the drugs in rat paw carrageenan assays) equal to or lower than indomethacin. In contrast, treatment with vehicle or 6-MNA resulted in no reductions in renal function. Conclusion: Administration of either celecoxib (specific COX-2 inhibitor) or indomethacin (selective COX-1 inhibitor) resulted in significant reductions in renal function. COX-2 specific inhibitors do not appear to lack the renal effects of NSAIDs.     

Differential effects of selective cyclooxygenase (COX)-1 and COX-2 inhibitors on anorexic response and prostaglandin generation in various tissues induced by zymosan

We have shown that anorexic response is induced by intraperitoneal injection of zymosan in mice, although the role of prostaglandins in this response is relatively unknown as compared with lipopolysaccharide (LPS)-induced anorexic response. Indomethacin (0.5 and 2.0 mg/kg), a non-selective cyclooxygenase (COX) inhibitor, as well as meloxicam (0.5 mg/kg), a selective COX-2 inhibitor, but not FR122047 (2.0 mg/kg), a selective COX-1 inhibitor, attenuated zymosan-induced anorexia. Zymosan injection elevated COX-2 expression in brain and liver but not in small intestine and colon. Meloxicam (0.5 mg/kg) and FR122047 treatment (2.0 mg/kg) similarly suppressed the generation of brain prostaglandin E(2) (PGE(2)) and peritoneal prostacyclin (PGI(2)) upon zymosan injection. PGE(2) generation in liver upon zymosan injection was suppressed by meloxicam (0.5 mg/kg) but not by FR122047 treatment (2.0 mg/kg). Our observations suggest that COX-2 plays an important role in zymosan-induced anorexia, which is a similar feature in LPS-induced anorexic response. However, non-selective inhibition by selective COX-1 and COX-2 inhibitors of brain PGE(2) generation upon zymosan injection does not support the role of COX-2 expressed in brain in zymosan-induced anorexic response. PGE(2) generation in liver may account for peripheral role of COX-2 in zymosan-induced anorexic response.     

Intestinal effects of nonselective and selective cyclooxygenase inhibitors in the rat

It is now widely recognized that nonsteroidal anti-inflammatory drugs (NSAIDs) may cause extensive damage to the intestine. The pathogenesis of NSAID-induced intestinal injury, however, is still controversial and both local irritant actions and cyclooxygenase (COX) inhibition have been proposed as underlying mechanisms. In this study we investigated further on NSAID-induced intestinal damage by using nonselective (indomethacin and ibuprofen), COX-1 selective (SC-560) or COX-2 selective (celecoxib) inhibitors. NSAIDs were administered orally to conscious rats and small intestinal injury was evaluated 24 h afterwards in terms of macroscopic and microscopic alterations, myeloperoxidase activity, lipid peroxidation, number of enterobacteria in the mucosa and epithelial mucin content. Oral administration of indomethacin (20 mg/kg) induced macroscopic and microscopic damage to the small intestine, increased translocation of enterobacteria from lumen into the mucosa, myeloperoxidase activity and lipid peroxidation. Ibuprofen (120 mg/kg), SC-560 (20 mg/kg), celecoxib (60 mg/kg) or the combination of SC-560 plus celecoxib did not cause any intestinal injury nor modified the number of bacteria in mucosal homogenates. SC-560 significantly increased both myeloperoxidase activity and lipid peroxidation, whereas celecoxib significantly reduced myeloperoxidase levels, while leaving unaltered lipid peroxidation. Finally, all NSAIDs, mostly indomethacin, increased neutral mucins and decreased acidic mucins in the intestinal goblet cells. These results indicate that inhibition of cyclooxygenase, although variably influencing mucosal integrity homeostasis, is not sufficient to initiate acute intestinal damage in rats. Moreover, topical mucosal injury induced by the NSAID molecule seems to be a critical factor in the development of intestinal injury.     

Different modulation by cyclooxygenase inhibitors of the response to angiotensin II in monkey arteries and veins

In coronary, renal and femoral arteries and mesenteric veins isolated from Japanese monkeys, tachyphylaxis to angiotensin (ANG) II (10(-7) M)-induced contraction rapidly developed. Contractions caused by ANG II in coronary arteries were attenuated by treatment with indomethacin and aspirin and also by endothelium denudation. Indomethacin inhibited the response of the arteries with and without endothelium to a similar extent. OKY 046, a thromboxane A2 synthesis inhibitor, failed to inhibit the response. In contrast, contractions of renal arteries were potentiated and prolonged by the cyclooxygenase inhibitors. ANG II-induced contractions of mesenteric veins were prolonged but those of femoral arteries were not altered by indomethacin. It is concluded that ANG II contracts monkey coronary arteries, possibly due to the release of vasoconstrictor prostanoids but not thromboxane A2 from endothelial and subendothelial tissues and also due to its direct action on smooth muscle, whereas contractions of renal arteries and mesenteric veins are blunted by vasodilator prostanoids, possibly PGI2. Cyclooxygenase products even if released do not appear to regulate femoral artery contractions produced by ANG II.     

Central and peripheral effects of angiotensin II on the cardiovascular response to exercise

The authors tested the hypothesis that angiotensin II modulates cardiovascular responses to dynamic exercise via peripheral and central effects on the autonomic nervous system. Ten subjects performed three identical exercise tests during treatment with placebo, valsartan (an angiotensin II type 1 receptor blocker), or enalapril (an angiotensin-converting enzyme inhibitor). With placebo, plasma concentrations of angiotensin II, norepinephrine, and epinephrine were elevated during cycling at 80% of heart rate reserve (HRR). Enalapril attenuated increases in heart rate, mean arterial pressure (MAP), and catecholamines during cycling, whereas valsartan only attenuated MAP and rate-pressure product above 60% HRR, and norepinephrine. The different responses provoked by the two drug treatments suggest that angiotensin-converting enzyme inhibition affects cardiovascular responses to exercise by mechanisms unrelated to production of angiotensin II. Indices of autonomic function during dynamic exercise were not changed by either drug. Attenuation of norepinephrine release during exercise by valsartan suggests that angiotensin II facilitates the release of norepinephrine from sympathetic postganglionic neurons. Angiotensin II, therefore, contributes to the pressor response to exercise by inducing peripheral vasoconstriction and facilitation of norepinephrine release from postganglionic sympathetic nerve endings that are unrelated to central activation of the autonomic nervous system.     

Acute cardiovascular response to monoamine oxidase inhibitors: a prospective assessment

Despite the widespread use of monoamine oxidase inhibitors (MAOIs) and the well-known adverse event of hypertensive crisis, few studies have addressed the acute cardiovascular response to an MAOI dose. We prospectively measured pulse and blood pressure changes just before and at 1, 2, 3, and 4 hours after MAOI administration in 18 patients. Significant but asymptomatic increases from baseline in mean systolic and diastolic blood pressure occurred within 2 hours after MAOI administration, with return to near baseline by 4 hours. The mechanism of this reaction is unknown.     

Cholesterol-like effects of selective cyclooxygenase inhibitors and fibrates on cellular membranes and amyloid-beta production

Strong evidence suggests a mechanistic link between cholesterol metabolism and the formation of amyloid-beta peptides, the principal constituents of senile plaques found in the brains of patients with Alzheimer's disease. Here, we show that several fibrates and diaryl heterocycle cyclooxygenase inhibitors, among them the commonly used drugs fenofibrate and celecoxib, exhibit effects similar to those of cholesterol on cellular membranes and amyloid precursor protein (APP) processing. These drugs have the same effects on membrane rigidity as cholesterol, monitored here by an increase in fluorescence anisotropy. The effect of the drugs on cellular membranes was also reflected in the inhibitory action on the sarco(endo)plasmic reticulum Ca(2+)-ATPase, which is known to be inhibited by excess ordering of membrane lipids. The drug-induced decrease of membrane fluidity correlated with an increased association of APP and its beta-site cleaving enzyme BACE1 with detergent-resistant membranes (DRMs), which represent membrane clusters of substantial rigidity. DRMs are hypothesized to serve as platforms for the amyloidogenic processing of APP. According to this hypothesis, both cholesterol and the examined compounds stimulated the beta-secretase cleavage of APP, resulting in a massive increase of secreted amyloid-beta peptides. The membrane-ordering potential of the drugs was observed in a cell-free assay, suggesting that the amyloid-beta promoting effect was analog to cholesterol due to primary effect on membrane rigidity. Because fenofibrate and celecoxib are widely used in humans as hypolipidemic drugs for prevention of atherosclerosis and as anti-inflammatory drugs against arthritis, possible side effects should be considered upon long-term clinical application.     

Modulation of circulatory responses to enkephalins by cyclooxygenase inhibitors

1. Experiments were undertaken to examine the hemodynamic effects of intravenously administered leucine and methionine enkephalin and to determine if prostaglandin synthesis is involved in these responses. 2. Intravenous administration of leucine and methionine enkephalin (10, 30 and 100 micrograms/kg) resulted in a dose dependent and transient decline in mean arterial blood pressure in pentobarbital anesthetized cats. 3. A significant difference was observed, however, between the hemodynamic responses to leucine and methionine enkephalins before sodium meclofenamate (1 mg/kg) administration compared to post-meclofenamate induced hemodynamic changes. 4. This was confirmed with ibuprofen. 5. These findings indicate that cyclooxygenase inhibition modulates the circulatory responses to enkephalins. 6. Since cyclooxygenase is the first enzyme in the biosynthetic pathway of arachidonic acid, it is possible that prostaglandins, endoperoxides, thromboxanes or other prostanoids may be involved in mediating the circulatory responses to enkephalins.     

Differential effects of factor IIa inhibitors on the endogenous thrombin potential

Calibrated automated thrombin generation measurement in clotting plasma (endogenous thrombin potential, ETP) is being used increasingly to monitor the effects of anticoagulant drugs. Calibrated automated thrombography measures the concentration of thrombin in clotting plasma by monitoring the cleavage of a fluorogenic substrate (Z-Gly-Gly-Arg-7-amino-4-methylcoumarin) and comparing it with a constant known thrombin activity in a parallel nonclotting sample. This study compared the concentration-dependent effects of different factor IIa inhibitors on the ETP. In accordance with a theoretical prediction, the monovalent factor IIa inhibitors melagatran and argatroban reduced peak thrombin concentrations without a marked effect on the lag time of thrombin generation. However, both bivalent factor IIa inhibitors lepirudin and bivalirudin markedly prolonged the lag time of thrombin generation and thus behaved like "super" factor Xa inhibitors according to the theoretical model. These findings have important consequences for therapeutic drug monitoring using thrombin generation assays. For monitoring of hirudins, the lag time of thrombin generation seems to be a very sensitive parameter. In contrast, for monitoring of argatroban, the evaluation of the ETP seems to be useful.     

Interspecies differences in the nephrotoxic response to cyclooxygenase inhibition

In contrast to cyclooxygenase-1 (COX-1), the basal expression of renal cyclooxygenase-2 (COX-2) varies among species. High basal levels of COX-2 in the renal cortex and papilla in dogs compared with monkeys suggest that COX-2 inhibition may lead to distinct nephrotoxic responses. In this study, we compared the renal effects of COX inhibition between dogs and cynomolgus monkeys (n = 6/group) following the administration of naproxen sodium, a non-selective COX-1/COX-2 inhibitor. Dogs and monkeys were treated with 50 or 150 mg/kg/day naproxen sodium, respectively, for 2 to 6 weeks. Naproxen doses used in this study resulted in equivalent inhibition of COX activity in both species as measured by reductions in urinary prostaglandin E2 (PGE2) and 6-keto-PGF1-alpha levels. There was prominent reduction in renal blood flow (43%) and urinary sodium excretion (62%) in dogs but no alterations in renal blood flow and only minimal change (19%) in urinary sodium excretion in monkeys. The canine but not monkey kidney showed prominent COX-2 expression in the macula densa, thick ascending limb of Henle and papillary interstitial cells by immunohistochemistry. After treatment, the canine but not monkey kidneys had mild to moderate renal tubular atrophy and interstitial fibrosis and renal papillary necrosis. Obstructive nephropathy secondary to intra-tubular drug accumulation was seen in monkeys but not in dogs. Collectively, these data demonstrate species differences in the renal response to COX inhibition. The nature of functional and morphologic changes suggests a more prominent role of COX-2 in renal hemodynamics and natriuresis in dogs than in monkeys.     

Differential effects of prostaglandin synthetase inhibitors on EEG in rat

The effects of five nonsteriodal prostaglandin (PG) synthetase inhibitors on the electrocorticogram were studied in rats with chronically implanted supracortical electrodes. All of PG synthetase inhibitors produced high voltage activity in the electrocorticogram. However, behavior and spectral analysis of the electrocortical activity suggests that these drugs could be divided into two groups. Meclofenamic acid and mefenamic acid produced dose-related increases in excitation (to seizure) while ibuprofen, paracetamol and indomethacin produced dose-related increases in sedation.     

Differential effects of antipsychotic and glutamatergic agents on the phMRI response to phencyclidine.

Acute administration of NMDA receptor (NMDAR) antagonists such as phencyclidine (PCP) or ketamine induces symptoms that closely resemble those of schizophrenia in humans, a finding that has led to the hypothesis that a decreased NMDAR function may be a predisposing or even causative factor in schizophrenia. However, the precise neuropharmacological mechanisms underlying these effects remain to be fully elucidated. Here, we applied pharmacological MRI (phMRI) to examine the brain circuitry underlying the psychotomimetic action of PCP in the anesthetized rat, and investigated how these functional changes are modulated by drugs that possess distinct pharmacological mechanisms. Acute administration of PCP (0.5 mg/kg i.v.) produced robust and sustained positive relative cerebral blood volume (rCBV) changes in discrete cortico-limbo-thalamic regions. Pretreatment with the selective D2 dopamine antagonist raclopride (0.3 mg/kg i.p.) did not significantly affect the rCBV response to PCP, while the atypical antipsychotic clozapine (5 mg/kg i.p.) produced region-dependent effects, with complete suppression of the rCBV response in the thalamus, and weaker attenuation of the response in cortical and hippocampal structures. The response to PCP was strongly suppressed in all regions by pretreatment with two drugs that can inhibit aberrant glutamatergic activity: the anticonvulsant lamotrigine (10 mg/kg i.p.) and the mGluR2/3 agonist LY354740 (10 mg/kg i.p.). Taken together, our findings corroborate the pivotal role of dysfunctional glutamatergic neurotransmission in the functional response elicited by PCP, while the lack of effect of raclopride argues against a primary role of dopamine D2 receptor activation in this process. Finally, the thalamic effect of clozapine could be key to elucidating the functional basis of its pharmacological action.     

Comparison of effects of cyclooxygenase inhibitors on myometrial contraction and constriction of ductus arteriosus in rats

The aim of this study was to compare the tocolytic effect of a selective cyclooxygenase-2 inhibitor, DFU (5,5-dimethyl-3(3-fluorophenyl)-4-(4-methylsulphonyl)phenyl-2(5H)-furanone), indomethacin and nimesulide on myometrial strips isolated from rats in both lipopolysaccharide-induced preterm labour and term labour. We also compared the constrictor effects of DFU and indomethacin on the fetal ductus arteriosus. Myometrial strips were obtained from preterm and term labour Wistar albino rats and were mounted in organ baths for the recording of isometric tension. DFU, nimesulide and indomethacin significantly inhibited KCl-, oxytocin-, prostaglandin E(2)- and prostaglandin F(2 alpha)-stimulated contractions of myometrial strips isolated from rats in preterm and term labour. The E(max) value of indomethacin was significantly lower than those for DFU and nimesulide (P<0.05), with no change-log (10) EC(50) values. There was no significant difference between in -log (10) EC(50) and E(max) values of DFU and nimesulide for any of the tissues (P>0.05). In addition, there was no significant difference between -log (10) EC(50) and E(max) values for each of these three agents in myometrial tissues isolated from rats in preterm and term labour (P>0.05). Fetal ductus arteriosus was significantly constricted by DFU (10 or 100 mg/kg) in preterm and term rats, although DFU (10 or 100 mg/kg)-induced constriction ratios were significantly lower than those for indomethacin (P<0.05). These data demonstrate that DFU, a specific cyclooxygenase-2 inhibitor, could be considered as a new therapeutic agent for preterm labour. However, careful attention should be given to constriction of the fetal ductus arteriosus.     

Celosomy is associated with prenatal exposure to cyclooxygenase inhibitors.

Celosomy is a term used for a group of congenital anomalies characterized by opening of the somatic wall with evisceration. The most common types of celosomy are gastroschisis and omphalocele. They have been associated with maternal age, cigarette smoking, environmental pollution, as well as prenatal exposure to vasoconstrictors and recreational drugs. The aim of this study was to evaluate the effect of prenatal exposure to various selective and non-selective cyclooxygenase-2 (COX-2) inhibitors on the abdominal wall defects in rat. A retrospective statistical analysis was performed on the basis of data collected in our laboratory in the years 1997-2004, during different teratological studies with COX-inhibitors (aspirin, DFU, DuP-697, ibuprofen, paracetamol, piroxicam, propyphenazone, tolmetin). Out of 6744 live born fetuses celosomy was revealed only in four animals exposed to different non-selective COX inhibitors. A single case of gastroschisis was also found in a rat exposed to the selective COX-2 inhibitor. The fetal body weight was significantly lower in COX-exposed group of fetuses when compared with untreated control. It was also significantly decreased in non-malformed fetuses prenatally exposed to COX inhibitors when compared with untreated control. The fetal body weight and length were lower in fetuses born with gastroschisis than with omphalocele. However, when animals with both anomalies were pooled in one group the mean fetal body weight was marginally lower (p = 0.0523) when compared with non-malformed group, while no statistically significant differences were found for fetal length. The pooled statistical analysis done for the concurrent and our own historic data showed that only aspirin statistically increased the risk of abdominal wall defects in rat fetuses. The expected ratio for aspirin is 56.41 per 10,000 offsprings (p < 0.05), which is over 10-times higher than ratio for all non-selective COX inhibitors, including aspirin (6.01/10,000; p < 0.05). No differences were found for selective COX-2 inhibitors. It could be stressed that aspirin, unlike other non-selective and selective COX-2 inhibitors increases the risk of the abdominal wall defects, which are observed more often in growth-retarded fetuses.     

Differential effects of inhibitors of purine metabolism on two trichomonad species

Tritrichomonas foetus and Trichomonas vaginalis are both incapable of de novo purine nucleotide synthesis. Previous studies indicated that T. foetus relies mainly on the salvage of hypoxanthine and subsequent conversion of IMP to AMP and GMP, whereas T. vaginalis depends on direct conversions of exogenous adenosine to AMP and guanosine to GMP without much interconversion between the two nucleotides. These two different types of purine salvage suggest the possibility of differential sensitivities between the two species of trichomonad flagellates toward different purine antimetabolites. Mycophenolic acid, hadacidin, 8-azaguanine, and formycin B inhibited the growth of T. foetus but had no effect on T. vaginalis. Mycophenolic acid acted by blocking conversion of IMP to GMP, hadacidin inhibited conversion of IMP to AMP, and 8-azaguanine was incorporated into the T. foetus nucleotide pool, likely via hypoxanthine phosphoribosyl transferase. Formycin B was converted to 5'-monophosphate in T. foetus and inhibited the conversion of IMP to AMP. Its precise mechanism of action on T. foetus remains, however, to be elucidated. Alanosine, whose ribonucleotide derivative is a potent inhibitor of adenylosuccinate synthetase, had no effect on the growth or hypoxanthine incorporation in T. foetus, which may be due to the lack of conversion of alanosine to the ribonucleotide because of the absence of de novo purine nucleotide synthesis in parasites. Four adenosine analogs, adenine arabinoside, tubercidin, sangivamycin, and toyocamycin, were found inhibitory to the growth of T. vaginalis but showed little effect on T. foetus growth. Further investigations suggested that these four compounds acted on T. vaginalis by blocking incorporation of adenosine into the adenine nucleotide pool.     

Influence of cardioprotective cyclooxygenase and lipoxygenase inhibitors on peroxidative injury to myocardial-membrane phospholipid

Oxygenase-catalyzed and non-enzymatic polyunsaturated fatty acid peroxidations have potential pathogenic roles in ischemic-reperfusion damage to the myocardium. Certain oxygenase inhibitors protect heart muscle from irreversible ischemic injury, and some antiperoxidants can inhibit oxygenase enzymes. We investigated the antiperoxidative abilities of eight anti-ischemic, cardioprotective oxygenase inhibitors to prevent myocardial-membrane phospholipid peroxidation through superoxide-driven, iron-promoted reactions with xanthine oxidase as the source of superoxide. Flurbiprofen, ibuprofen, and REV-5901-5 did not affect peroxidation at concentrations up to 1000 microM. BW755C, AA-861, nafazatrom, dipyridamole, and propyl gallate did protect and cardiac lipids against oxidative injury in a concentration-dependent manner with respective and antiperoxidant IC50 values (concentrations at which peroxidation was inhibited by 50%) of 0.22, 1.25, 3.0, 3.6 and 50 microM. Catechin and phenidone, known oxygenase inhibitors not yet evaluated as anti-ischemic agents, were also found to be antiperoxidants at low micromolar concentrations. Four cyclooxygenase inhibitors ineffective against myocardial infarction (aspirin, indomethacin, naproxen, and sulfinpyrazone) evidenced no antiperoxidant properties at concentrations up to 500 microM. The oxygenase inhibitor-antiperoxidants identified could neither quench superoxide radical nor inhibit xanthine oxidase. However, they were able to interrupt the propagation of an on-going peroxidation reaction. Their antiperoxidant profiles resembled those of known antioxidants, such as alpha-tocopherol, which inhibit peroxidation by intercepting lipid free-radical intermediates. These data raise the possibility that at least some oxygenase inhibitors could exert cardioprotective effects by directly influencing the sensitivity of myocardial-membrane phospholipid to peroxidative injury. Consequently, recognition of the antiperoxidant properties of these agents may aid dissection of their physiological and pharmacological actions.     

Risk factor-induced cardiovascular remodeling and the effects of angiotensin-converting enzyme inhibitors

Cardiovascular (CV) risk factors, primarily arterial hypertension, modify the structural and functional features of the myocardium and the blood vessels, a process known as CV remodeling. Cardiac remodeling refers to changes in left ventricular (LV) geometry, such as concentric LV geometry and LV hypertrophy (LVH), an independent hallmark of CV risk. Vascular remodeling consists of structural changes of the arterial walls, such as increased intima-media thickness, arterial stiffening, and deteriorating endothelial function. CV remodeling is to a large extent a result of compensatory mechanisms, and its pathophysiology is partially mediated by the activation of the renin-angiotensin-aldosterone system and its primary effector peptide angiotensin II, which together play a key role in the progression of CV disease. Angiotensin-converting enzyme (ACE) inhibitors, a class of drugs used in the treatment of arterial hypertension, appear to be effective in controlling or even reversing CV remodeling, independently of simple blood pressure reduction. Evidence shows that ACE inhibitors counteract CV remodeling by reducing LV mass and regressing LVH, attenuating vascular atherosclerosis and improving vascular compliance. ACE inhibitors possessing a sulfhydryl moiety appear to have additional benefits in increasing nitric-oxide release and improving vascular endothelial function.